Arrhythmias are abnormal heart rhythms that occur either in the atria or the ventricles. Arrhythmias arising in the atria are called atrial arrhythmias, and these disorders include atrial fibrillation, atrial flutter, and paroxysmal atrial tachycardia (PSVT). Arrhythmias arising in the ventricles, known as ventricular arrhythmias, are a group of disorders having diverse etiologies, including idiopathic ventricular tachycardia, ventricular fibrillation, and Torsade de Pointes (TdP). Arrhythmias can range from incidental, asymptomatic clinical findings to life-threatening abnormalities, and account for a significant percentage of the causes of death in humans. Thus, it is desirable to develop methods of mitigating the effects of arrhythmias.
A variety of anti-arrhythmic drug therapies are presently available, and are classified as follows. Class I anti-arrhythmics, comprising sodium channel blockers; Class II, comprising beta-blockers; Class III, comprising drugs that prolong action potential (usually by blocking potassium channels); and Class IV, comprising calcium channels blockers. Cardiac glycosides, for example digitalis, are also used as drugs for the treatment of arrhythmia, but they have a delayed onset of action (about 30 minutes) and their peak effects are not observed for ≧3 to 4 hours after administration. Additionally, digitalis is toxic at doses close to the therapeutic dose, which limits the utility of the compound.
In fact all of the above classes have significant limitations. For example, beta-blockers, such as propranolol and esmolol, and calcium-channel blockers, for example verapamil, bepridil, and diltiazem, can cause hypotension, potentially have negative inotropic effects, and may also precipitate new arrhythmias, including TdP.
Adenosine, which is widely found in nature, is another compound that has anti-arrhythmic activities, by virtue of its ability, at certain dose levels, to slow the conduction in the atrioventricular node. The anti-arrhythmic effects of adenosine are due exclusively to its interaction with the adenosine A1 receptor subtype. However, although adenosine is highly effective in ameliorating arrhythmia, it also binds contemporaneously to other adenosine receptor subtypes (A2A, A2B, and A3), which results in undesirable side effects, such as vasodilation, changes in the heart rate, mast cell degradation, etc. Adenosine also has a short half-life (˜10 sec), making it ineffective in treating conditions that require prolonged action.
Compounds that are selective agonists for adenosine A1 receptors are known. For example, a new class of agonists that bind to adenosine A1 receptors and that are useful in treating arrhythmias are disclosed in U.S. Pat. No. 5,789,416, and in U.S. patent application Ser. No. 10/194,335, the entire disclosures of which are hereby incorporated by reference. These compounds have a high specificity for the adenosine A1 receptor subtype, but like all therapeutic compounds, can potentially cause side effects.
Antiarrythymic agents in general have a narrow margin between the dose required to produce the desired antiarrhythmic effect and the dose that produces an adverse effect. It would therefore be desirable to find a method of treating arrhythmia that is effective at low doses (or minimal doses) of the active agent, thus decreasing the likelihood of adverse effects. We have discovered that low doses of adenosine A1 receptor agonists, preferably partial agonists, and more preferably selective adenosine A1 receptor agonists, can be used in combination with low doses of beta blocker, calcium channel blockers, or cardiac glycosides, to provide an effective treatment for arrhythmia that minimizes the side effects of beta blockers, calcium channel blockers, cardiac glycosides, and A1-adenosine receptor agonists that may potentially occur when taken individually. It has also been observed that at low doses, the combination of these agents act in a synergistic manner, thus reducing even further the chance of side effects. It has also been observed that the combination of an A1 adenosine receptor antagonist with a beta blocker can be used in the treatment of heart failure, including ischemic heart disease, congestive heart failure, heart failure syndrome, hypertension, and the like.
Accordingly, a novel and effective method of treating arrhythmias is provided that restores sinus rhythm without slowing the sinus rate and is virtually free of undesirable side effects, such as changes in mean arterial pressure, blood pressure, increased heart rate, TdP, or other adverse effects.